Clinical role of MRS quantification of 2HG in diagnosis of malignant gliomas and assessment of therapy response
Project Allocated in 2016-2017
The evaluation of glioma therapies relies on quantifying response rates. Gliomas with mutant IDH (isocitrate dehydrogenase) present a metabolic alteration resulting in overproduction of the oncometabolite 2-hydroxyglutarate (2HG). Recent evidence demonstrated that IDH mutation coupled with elevated 2HG levels has also positive prognostic value. 2HG is thus an ideal biomarker to probe treatment response in IDH-mutant glioma patients.
Conventionally, IDH mutation is determined by the immunohistopathology in tumour tissue samples obtained by biopsy or (sub)total tumour resection. Theoretically, Magnetic Resonance Spectroscopy (MRS) offers a sensitive tool to detect and quantify an array of metabolites, including 2HG, in tumours and thus non-invasively determine wild type or mutated IDH status. Some research groups have recently validated their methods for reliable 2HG estimation in vivo. We have set up a collaboration with Massachusetts General Hospital (MGH) (Boston, MA, USA) to use their state-of-the-art MRS methodology to obtain whole-tumour 3D maps of 2HG during clinical routine exams .
The PhD project will focus on assessing and re-validating the impact of this 3D MRS-Imaging sequence on determining the IDH mutation status, on quantifying the 2HG concentration in vivo, and on guiding therapy monitoring. Our aim is the clinical implementation of the new MRS technique at UCLH for non-invasive primary staging and treatment monitoring of brain tumours. The project will be based at the National Hospital for Neurology and Neurosurgery, will mainly utilise two 3T Siemens scanners (3T Prisma and 3T Skyra) and will require developing experience in acquiring and analysing MR spectra; it may also involve MR sequence programming as well as the acquisition of high-resolution (nuclear magnetic resonance) NMR spectroscopy measurements for ex vivo validation of the acquired 3D-MRS results in tumour tissue samples.
The methodology that is the focus of this project has great potential to provide an accurate, non-invasive biomarker with high sensitivity/specificity for early diagnosis and staging of gliomas as well as for monitoring treatment response. Once fully clinically validated, non-invasive MRS assessment of IDH mutation may eventually allow to spare the invasive surgical biopsy at the baseline, i.e. patients who present with tumours in eloquent areas where surgical intervention is associated with increased morbidity, and on surveillance, where the patient morbidity is also increased due to the therapy-related tissue injury. The methodology will support clinician in designing personalised treatment plans. Using MRS to test the response to established or novel therapeutic treatments will also reduce the need for further/repeated invasive biopsies.